cell based therapy- a novel, upcoming, research level therapy for traumatic brain injury

1. Dr. Malaka Munasinghe
Registrar in Anaesthesia
2015.09.17

2. Significance!!!
USA stats by 2010
-2 million visits to ETU
- 0.3 million admissions
- 55,000 deaths ( 30% of all injury related deaths)
- COST
76 BILLION DOLLARS

3. Current lines of Management
-supportive
- Focus on,
reducing secondary brain damage
- No effective definitive therapy
BUT - EMERGING
CELL BASED THERAPY

4. Pathophysioloy of TBI
Mechanism
-Direct impact
- Acceleration and deceleration/ rotational forces
- Primary phase
- Secondary phase

5. Primary phase
-immediate
- Massive neuronal depolarization
Release of neurotransmitters
- monocyte/macrophage mediated phagocytosis
- Complement mediated cytolysis
- Diffuse neuronal dysfunction

6. - disrupted blood brain barrier
- Expressed GLUT-1
- Synthesis and release of NO
cerebral vasodilatation
ICP
Worsen primary brain injury

7. Secondary phase
- Few hours after TBI
- Last several days
- Intracellular Ca2+ influx
- Free radical formation and lipid peroxidation
- Mitochondrial dysfunction
-Neuronal apoptosis ( focal and diffuse)
hippocampus- more vulnerable

8. - Upregulation of NGF/BDNF
- Downregulation of neutrophin-3 advantageous
BUT,
- NOT EFFECTIVE for Endogenous stem cell function
In repairing
AS,
Acute inflammatory enviorenment after TBI
( May last several weeks)

9. CELL BASED THERAPY FOR TBI
Cell types used
 Mesenchymal stem cells(MSC)
 Neural progenitor cells(NPC)
 Ntera 2(NT2) cells
 Embryonic stem cells
 Multipotent adult progenitor cells
 Endothelial progenitor cells

10. Mechanisms of action of cell based therapy
 Differentiaton in to locoregional cells
 Reduction of oedema and inflammation in TBI
 Secretion of chemokine and growth factors
 Enhancing neurogenesis,angiogenesis and
vasculogenesis
 Stabilizing damaged cells by gene and protein
transfer (fusion or intercellular contact)
 Enhancing migration of host neurogenic cells to the
area of TBI

11. Delivery of cells
 Intravenous
 Lateral ventricle
 Internal carotid artery
 Stereotactic method

12. Scaffolds used for cell delivery
 Fibrin
 Matrigel
 Collagen
 Gelatin
( provides an extracellular matrix
Maintain viability)

13. Timing of delivery of cells
 Just after the TBI to one week after
 No study analysing effectiveness in different timings
 BUT-
even with late administrations- improvement +

14. Assessment of improvement(ANIMAL MODELS)
 Motor function ; stepping or balance beam tests
 Learning ability ; morris walter maze test
 Reduction in cerebral lesion volume
- histology
- MRI/PET
 Reduced proinflammatory cytokines(IL1/6/TNF α)

15. CURRENT CLINICAL TRIALS
 Cox and colleagues- 2011
- prospective, non-random ,open label, phase 1/2
trial
- 1O chlidren aged 5-14 years with post resuscitation
GCS-58
- Autologus bone marrow derived cells
- administered 48 hrs later/followed up to 6 months
- three patients –complete recovery

16. Cox and colleagues- 2011 ctd…
BUT
ALL- SOME NEUROLOGICAL IMPROVEMENT!!!
-No post injury seizures
- No refractory intracranial pressure
-No new ischemic events
- No alteration in CPP

17. Tian and colleagues 2013…
- prospective, non-random ,open label, phase 1/2
trial
- 97 patients in subacute phase of TBI
- Intrathecal administration of autologus bone marrow
derived cells 02months after the injury
- Followed up for 40 days
- ¼-improved motor functions
- 11 out of 24 patients in vegetative state- improved
consciousness

18. Ongoing trials +++
One- to determine optimal route for delivery of cells

19. Concerns….
- Optimal route and timing yet to be deciced
- Stereotactic administration- invasive/need a
neurosurgeon
- Monitoring parameters to assess safety and efficacy
options - MRI to assess cerebral perfusion+ lesion
- concnt. of systemic pro and anti
inflammatory markers
- comprehensive neurological testing
- assessing functional recovery of
hippocampus

20. - gnerating,processing ,storage of stem/progenitor
cells- costly
- Difficulty in differentiating iatrogenic tumour foci
from inflamed tissue

21. Summary
- Traumatic brain injury is a major public health issue
- Cell based therapy would be a promising approach
- Animal and phase 1/2 human trials have shown
positive results
- Though, more studies are needed in understanding
the therapeutic mechanisms of stem cell therapy.

22.  References
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23. THANK YOU….